Health and longevity are maintained, at least in part, by secreted peptides signaling metabolic condition at a cellular and organismal level. The secreted peptide adropin was identified by the Butler laboratory in 2008 as such a signal. The long-term goal of the Butler (PD/PI) lab is to advance knowledge of the specific functions of adropin. The Butler laboratory has been a leader in studying the involvement of adropin in metabolic control, showing that the putative secreted domain (adropin34-76) rapidly alters activity of intracellular signaling molecules (e.g., SIRT1, Pgc1alpha) regulating glucose and fatty acid metabolism. While adropin is most abundant in the central nervous system, its functions as a neuropeptide remain unknown. The current proposal addresses this gap in knowledge by leveraging the combined resources of three laboratories at Saint Louis University to School of Medicine. The long-term goal of the Farr (CoInv.) lab is to advance knowledge of the neural signaling pathways involved in dementias. The Chakraborty lab (Co-Inv.) brings extensive experience in assessing mechanisms of intracellular signaling in vivo. Preliminary data obtained using a newly developed Cre-inducible reporter mouse suggests that adropin is expressed in hippocampal neurons. Pilot studies using a transgenic mouse strain over expressing adropin (AdrTG) in the brain and periphery suggest a delay or prevention in the decline in learning and memory with aging. Altered expression of the active/inactive isoforms of glycogen synthase kinase3-beta (GSK3beta) and reduced Ser396 phosphorylation of the tau protein, which stabilizes microtubules in neurons, suggesting reduced kinase activity in AdrTG provides a hypothetical mechanism for improved cognitive function. The objectives of this application while exploratory will establish whether adropin acts in the central nervous system to regulate or maintain cognitive function by pursuing the following two SPECIFIC AIMS: (1) Investigate whether signaling pathways linked to cognitive function respond acutely to centrally administered adropin34-76. Once AIM 1 is completed, we will have established whether adropin signaling acutely regulates intracellular signaling cascades and kinases known to affect tau phosphorylation in the nervous system (GSK3beta, CDK5), and whether exogenous adropin3476 administered directly into the CNS improves cognitive performance in lean healthy male and female B6 mice. This AIM will also determine whether exogenous adropin treatment can improve cognitive performance in situations where the mental acuity of mice is impaired by aging, or by diet-induced obesity. (2) Determine whether improved cognitive function of aged AdrTG associates with or is independent of improved whole body metabolic control, and determine whether loss or reduced adropin signaling impairs cognitive performance with aging. Few options are currently available for the treatment of dementias that are becoming increasingly common in an overweight, aging population. These experiments will yield new information on the prospective role of a peptide hormone in cognitive function, and may provide a foundation for developing new treatments for dementia.